The retinal pigment epithelial (RPE) cell plays a basic role in maintaining the structural and physiological integrity of the neural retina. Alterations in its structural and functional actions can result in loss of photoreceptors and vision. We have studied the RPE cell extensively as an important immunoregulatory cell within the posterior pole of the eye. Our research activities on RPE cells can be subdivided into three categories: normal cell function studies, cytokine interactions and infectious processes. This project has concentrated on studying the ways in which cytokines interact with cells of the immune system and with cells in the ocular microenvironment. These studies indicate that cytokine-mediated activation of RPE cells may be a basic component of ocular immunity and an important aspect of RPE cell transplantation. During the past year, we have studied the regulation of immune reactivity in the retina. The RPE cell plays a pivotal role in immune defense, since it orchestrates both innate and adaptive immunity. However, since an uncontrolled inflammatory response within the retina can itself lead to cellular damage, a down regulatory force is needed to limit immunopathologic damage. This may be an essential element in diseases such as AMD. We hypothesize that IFN-beta;, IL-11 and TGF-alpha;produced by the RPE cell are critical components of that limiting force. The aim of our studies was to define and elucidate the factors that trigger IL-11 and IFN-beta;production in human RPE cells and to identify mechanisms by which these cytokines exert immunoregulation. We have identified three different aspects of immunoregulatory actions of IFN-beta. (1) IFN-beta inhibits gene expression and protein production of CXCL9 and ICAM-1 in a variety of human and mouse cells (including: RPE, retinal vascular endothelial cells, glia, neuroblastoma, macrophage). In contrast, CXCL10 and 11 are not inhibited.(2) IFN-beta treatment increases survival in experimental cerebral malaria in mice. Mechanisms of action: down-regulation of CXCL9 and ICAM-1 gene expression in the brain, down-regulation of CXCL9 expression on brain endothelial cells, decrease leakage in BBB, decreased migration of T cells to the brain, decrease expression of CXCR3 on T cells in spleen. (3) IFN-b treatment inhibits ocular inflammation in Th1 model system. Mechanism of action: decreased expression of CXCR3 on Th1 cells. These results indicate a critical role for RPE-cell derived IFN-beta that inhibits CXCL9 and ICAM-1 expression in the retina and suggest that this inhibition is an immuno-suppressive mechanism that protects the retina from excessive inflammation and damage. During the past year we have also Identified and characterized RPE cell production of the immunosuppressive cytokine IL-11. IL-11 gene expression and protein release is up regulated in human RPE cells treated with TGF-beta;, IL-1 and TNF-alpha;. Production is down regulated by IFN-gamma. Studies are ongoing to evaluate immune suppressive actions of IL-11. Thus, a better understanding of the immunoregulatory actions of IL-11 and IFN-beta may provide insight into novel therapeutic modalities and interventive strategies. Moreover, studies are on going to determine whether defects in the RPE immune suppressive functions are associated with chronic inflammation in retinal diseases, such as, AMD.